Cancer, also known as malignant tumor, is one of the highest morbidity and mortality in the world. It is characterized by abnormal cell proliferation and metastasis, which spread and metastasize in a short time or relatively short time after onset. Traditional treatment options include resection (if resection conditions are met), radiation therapy, and chemotherapy. The targeted therapy developed in recent years has the advantages of reducing toxicity, negative effects on patients, and improving survival rate. However, the use of targeted drugs will produce resistance for a period of time, and then the growth of cancer cells will spread very rapidly. Common cancers are: blood cancer, lung cancer, liver cancer, bladder cancer, rectal cancer, stomach cancer, and so on.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease that is confined to the lungs and occurs in the middle-aged and elderly population. Its lung histology and/or High-resolution chest CT (HRCT) is characterized by common interstitial pneumonia (UIP), and the cause is unclear. As a chronic interstitial lung disease, IPF onset is concealed, the condition is gradually worsened, and it can also be manifested as acute exacerbation. The average survival after IPF diagnosis is only 2.8 years, and the mortality rate is higher than most tumors. IPF is called a “tumor-like disease”.
Nonalcoholic fatty liver disease (NASH) refers to the clinical pathological syndrome characterized by excessive deposition of intrahepatic fat due to alcohol and other well-defined liver-damaging factors, and acquired metabolic stress liver injury closely related to insulin resistance and genetic susceptibility. With the global trend of obesity and its related metabolic syndrome, nonalcoholic fatty liver disease has become an important cause of chronic liver disease in developed countries such as Europe and the United States and in rich areas of China. The prevalence of NAFLD in ordinary adults is 10% to 30%. Among them, 10% to 20% are NASH, and the latter has a cirrhosis rate of 25% within 10 years. Non-alcoholic fatty liver disease can directly lead to decompensated cirrhosis, hepatocellular carcinoma and transplanted liver recurrence, and can also affect the progression of other chronic liver diseases, and participate in the onset of type 2 diabetes and atherosclerosis. Metabolic syndrome-related malignancies, atherosclerotic cardiovascular and cerebrovascular diseases, and cirrhosis are important factors influencing the quality of life and life expectancy of patients with nonalcoholic fatty liver disease. To this end, nonalcoholic fatty liver disease is a new challenge in the field of contemporary medicine, and the risk of non-alcoholic fatty liver disease to human health will continue to increase in the near future.
With the progress of research on tumor molecular biology, our understanding on the molecular mechanism of tumorigenesis and development, as well as different pathogenic targets, has deepened. In many information transmission and pathways involved in the induction of cancer, protein kinases are a class of biologically active organisms that catalyze the transfer of the gamma phosphate of ATP to the residues of many important proteins, phosphorylate them, and thus transmit signals, thereby participating in a series of Cell activity is closely related to cell growth, differentiation and proliferation. The development of selective protein kinase inhibitors to block or regulate diseases that are abnormal due to these signaling pathways has been recognized as an effective research strategy for anticancer drug development. Several protein kinase inhibitors were validated in clinical trials, and were approved for marketing.
The epidermal growth factor receptor tyrosine kinase (EGFR) is a transmembrane glycoprotein composed of 1186 amino acids and encoding a molecular weight of 170-kDa. EGFR can mediate multiple signaling pathways and transmit extracellular signals into the cell, which plays an important role in regulating the proliferation, differentiation and apoptosis of normal cells and tumor cells (Cell, 2000, 100, 113-127). EGFR is a constitutive expression component of many normal epithelial tissues (such as skin and hair follicles), and in most solid tumors, EGFR is overexpressed or highly expressed. For example, in lung cancer, the expression rate of EGFR ranges from 40 to 80%. Therefore, selectively inhibiting EGFR and interfering with its signal transduction pathway can achieve the purpose of treating lung cancer, and opens up a feasible way for targeted treatment of lung cancer. Clinically, combined with traditional radiotherapy and chemotherapy, first-line drugs with EGFR-targeted drugs such as gefitinib (Iressa®) and erlotinib (Tarceva®) have proven to be very effective in the treatment of lung cancer. However, the use of these drugs will lead to acquired resistance within 6-12 months. The resistance of approximately 50% of cases is related to a mutation in one amino acid residue in the EGFR kinase domain (mutation of the 790 threonine residue to methionine, T790M) (The New England Journal of Medicine, 2005, 352, 786-792). The T790M mutation results in steric hindrance when the inhibitor binds to EGFR or increases the affinity of EGFR to ATP, making the anticancer effect of such reversible binding competitive inhibitors greatly diminished. The emergence of drug resistance not only reduces the patient's sensitivity to drugs, but also greatly reduces the quality of life of cancer patients. Therefore, studies targeting other targets including inhibitors of other protein kinases are even more important.
The spleen tyrosine kinase (SYK) gene was first cloned from pig spleen cDNA in 1991 and encodes a non-receptor protein tyrosine kinase. The human SYK gene is located in the q22 region of chromosome 9, and the SYK protein contains 635 amino acids. It plays an important role in autoimmune diseases and hematological malignancies. For example, SYK gene can inhibit the proliferation and metastasis of malignant tumor cells such as breast cancer, melanoma and liver cancer. Currently, SYK inhibitors have been used in clinical phase II/III trials of rheumatoid arthritis, chronic lymphocytic leukemia, and the like. Recent studies have shown that the use of SYK inhibitors or interference with the expression of the SYK gene can effectively slow the progression of liver fibrosis/hardening and has a good therapeutic effect (see CN 105664178A).
Focal Adhesion Kinase (FAK) is a non-receptor tyrosine protein kinase that was identified in 1992 as a highly phosphorylated protein associated with the oncogene v-src, located in normal cells enriched with integrin adhesion areas. FAK is a key molecule in the cell's important cytoskeletal proteins and various signaling pathways, and plays an important role in cell survival, proliferation, migration and invasion. A number of scientific studies have shown that FAK inhibitors may be effective anti-tumor drugs. Recent scientific studies have also shown that FAK inhibitors may also be effective in the treatment of pulmonary fibrosis.
AXL is an important tyrosine receptor kinase, with full name in English of AXL receptor tyrosine kinase. AXL is also called UFO/ARK/Tyro, and its ligand is vitamin K-dependent growth promoting factor GAS6. The first discovery of AXL was as a transforming gene for chronic myeloid leukemia (CML). AXL, is overexpressed in metastatic colon cancer, thyroid cancer, breast cancer, prostate cancer, and melanoma. Inhibition of AXL activity can inhibit tumor growth, spread and metastasis.
FLT-3 (Fms-related tyrosine kinase 3) belongs to a family member of the type III receptor tyrosine kinase and is a signaling molecule. FLT-3 is expressed in various tissues such as liver, spleen, lymph, brain, placenta and gonads, and is also expressed in normal bone marrow cells and lymphoid cell precursors, and is expressed in many hematopoietic malignancies. Its signal transduction pathway is associated with many tumor conduction pathways. Therefore, FLT-3 has become an ideal anti-tumor drug target.
Cell cycle is mainly influenced by a series of serine/threonine kinases called Cyclin-dependent kinases (CDKs), which promote cell cycle progression, transcription of genetic information, and normal cell division and proliferation via the combination of themselves with subunit cyclins (cydins). CDK4/6 is a key regulator of the cell cycle that triggers a shift in the cell cycle from the growth phase (G1 phase) to the DNA replication phase (SI phase). During cell proliferation, a complex of cyclin D (Cyclin D) and CDK46 is capable of phosphorylating retinoblastoma protein (Rb). The tumor suppressor protein Rb phosphorylates to release its transcription factor E2F, which binds tightly in an unphosphorylated state. E2F activation further promotes cell cycle through the restriction point (R point) and progresses from G1 phase to S phase, entered the cycle of cell proliferation. Therefore, inhibition of CDK4/6 prevents the formation of the Cyclin D-CDK4/6 complex, which can block the progression of the cell cycle from the G1 phase to the S phase, thereby achieving the purpose of inhibiting tumor proliferation.
Janus kinase (JAK) is a cytoplasmic tyrosine kinase that transduces cytokine signaling from membrane receptors to STAT transcription factors. Scientific research has shown that inhibition of JAK can be a promising target for anticancer drugs.
In summary, the development of novel protein kinase inhibitors is of great significance.